We have reported that CDId-mediated antigen presentation is reciprocally-regulated by the MARK p38 and ERK1/2. Furthermore, a vaccinia virus (W) infection results in the rapid activation of p38, with a concomitant inhibition of antigen presentation by CD1d. Alterations in the intracellular localization of CD1d occur within 2 - 4 hfollowing aW infection; a similar effect is observed when the ERK pathway is inhibited. At later times post-infection, we see activation of ERK as well as JNK. In recent studies, we have found that another protein kinase, protein kinase C 8 (PKCS) plays an important role in regulating antigen presentation by CD1d, and it has been reported that PKC8 "links up" with MARK in the control of various cellular functions. Activating PKC8 largely preserves the reduction in antigen presentation by CD1d following a W infection. Furthermore, the cytokine transforming growth factor p (TGFp) can blunt the generation of antiviral effector cells and can activate the PKC8 and MARK signaling pathways. Thus, TGFp may exert critical control over signal transduction molecules and pathways that are essential to the host's immune response to a virus infection. Our preliminary data suggest that TGFp inhibits antigen presentation by CD1d. Considering the potential interdependence of a number of different signal transduction pathways, our objective is to investigate the mechanisms by which a W infection affects these pathways and, as such, their functional effects in the innate immune response. Our ultimate hypothesis is that antigen presentation by CD1d is regulated by a cooperative interplay between MARK and PKC8, which is disrupted following a W infection. To address this hypothesis, the following aims are proposed: 1. Determine the mechanism(s) by which the W B1Rkinase inhibits CDId-mediated antigen presentation and 2. Analyze the role(s) of PKC8 in the regulation of CDId-mediated antigen presentation in W-infected cells. These studies will further our understanding of how signal transduction pathways regulate antigen presentation and how viruses can disrupt them as a means of evading the host's innate antiviral immune response, with important applications to the development of new generation poxvirus vaccines and antiviral chemotherapy. RELEVANCE (See instructions): This project will investigate how vaccinia virus evades the host's innate antiviral immune response of the host. The knowledge gained will be applicable to the development of new and more effective vaccines against a number of different viruses as well as other infectious diseases and cancer.